The ability of the female sex steroids, namely estrogens and progesterone, to inhibit fertility in mammals has been known for many years. The primary mechanism involved is the inhibition of ovulation although many other steps in the reproductive process are vulnerable to alterations in the normal circulating patterns of these hormones. Inhibition of ovulation derives from the effect of the sex steroids on the hypothalamic-hypophyseal axis where they may inhibit synthesis and/or release of gonadotrophin releasing factors (LHRH) and/or the gonadotrophins (luteinizing hormone-LH, follicle stimulating hormone-FSH) themselves.
The natural sex hormones are seldom used to control fertility in mammals including man because of their weak oral activity which necessitates a daily injection schedule. Not until the development of potent orally active estrogens and progestational agents did this method of fertility control assume commercial significance.
Combination oral contraceptives are the most commonly used method for the hormonal suppression of fertility. These drugs contain small quantities of a synthetic estrogen and progestogen and are taken daily for twenty or twenty-one days of each menstrual cycle. While cycle control is usually excellent with these preparations, a host of side effects, some of them serious, have been associated with their use. Progestin-only contraceptives lack many of the side effects of the combination pills but are less effective in preventing pregnancy as well as in producing regular menstrual cycles. Long-acting synthetic progestational agents are effective for several months following a single intramuscular injection but are also associated with abnormal bleeding episodes or, in some cases, the absence of bleeding altogether (amenorrhea). Thus the greatest drawback of the currently available long-acting progestational agents in the control of fertility is their induction of a broad spectrum of aberrant bleeding problems. These bleeding problems may be controlled to some extent by the administration of estrogens at periodic intervals in the treatment cycle.
For many years researchers have sought a compound which is both progestational and estrogenic in nature with the hope that this single drug entity would be not only efficacious in controlling fertility but permit control of uterine bleeding. Such a compound would obviate the need for additional estrogen to control bleeding problems.
Norethindrone (17.alpha.-ethynyl-19-nortestosterone) was one of the first synthetic progestational agents to be incorporated into oral contraceptive tablets. In combination with ethynylestradiol or ethynylestradiol-3-methyl ether (mestranol), norethindrone has become one of the most widely used and accepted oral contraceptives in the world. It has long been known that esterification of the 17-hydroxyl group with long chain fatty acids yields compounds with prolonged hormonal activity. The heptanoate ester of norethindrone (norethindrone enanthate) is a long-acting progestational agent and contraceptive but its use has been associated with abnormal bleeding problems characteristic of progestogen-only contraceptive methods. 7.alpha.-Methylation of norethindrone confers substantial estrogenic activity on the parent molecule. 7.alpha.-Methylnorethindrone enanthate exhibits both progestational and estrogenic activity and has been shown to interfere with certain reproductive processes in experimental animals for extended periods of time.